increased cpa6 promoter methylation in focal epilepsy and in febrile seizures
TRANSCRIPT
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INCREASED CPA6 PROMOTER METHYLATION IN FOCAL
EPILEPSY AND INFEBRILE SEIZURES
Annick Salzmann, PhDService de Médecine Génétique (HUG)Département de Psychiatrie (UNIGE)
7ème Journée de la Recherche Clinique8 mai 2014
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• Epilepsy
• Focal Epilepsy & Febrile Seizures
• Carboxypeptidase A6 (CPA6)
• Epigenetics of epilepsy
• CPA6 DNA Methylation & Epilepsy
• Perspectives
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EPILEPSY
• Chronic neurological disorder à affects all ages
•Defined by 2 or more unprovoked seizures
• 50 million people worldwide (WHO 2009)
• 0.5–1% world population
• Epileptic phenomenen
‣ Hyperexcitability & Hypersynchrony
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FOCAL EPILEPSY
• Most common form of epilepsy (60%)
• Localisation-related – Temporal lobe epilepsy
• Resistance to anti-epileptic drugs
• Surgical resection of anterior temporal lobe structures
• Antecedent of febrile seizures
• Complex disorder = genetic + environment
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FEBRILE SEIZURES
• Not considered to be an epileptic condition
• Provoked by fever (>38.5°)
• Prevalence: 2–5%
• Onset age: 3 months and 5 years
• Epilepsy occurs 2–10 times more
• Important genetic predisposition
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CONSANGUINEOUS FAMILY
7
Complex Febrile Seizures + Temporal Lobe Epilepsy
Complex Febrile Seizures
One Simple Febrile Seizure
Several Simple Febrile Seizures
1 2
5
3 4 5 6
4
II
III
1 2 3 6 7 8 9 10
I M/– M/–
M/– M/–
Founder mutation = M
M/M M/M M/M M/MM/–or –/–
M/–or –/–
M/–or –/–
M/–or
M/M
Common Ancestor
Autosomal Recessive Model
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CARBOXYPEPTIDASE A6 (CPA6) MUTATION
CPA6 Protein
Salzmann et al. Hum Mutat, 2012
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CARBOXYPEPTIDASE A6 (CPA6)
• Member of the M14 metallocarboxypeptidase family
• Highly expressed in human embryonic brain and in fetal umbilical cord blood (Wei et al., J. Biol. Chem. 2002)
• 50-kDa pro-CPA6 → 37-kDa active form secreted into the extracellular matrix (Lyons et al., J. Biol. Chem. 2008)
• Cleaves C-terminal hydrophobic residues → role in neuropeptides regulation (Lyons et al., J. Biol. Chem. 2008)
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CPA6 MUTATIONS IN EPILEPTIC PATIENTS
CPA6 Protein
7 missense variants
Consanguineous FEB11/ELT5 familyc.809C>T → TT
3 FE patientsc.799G>A → GA1 TLE patient
c.843A>G → AG
1 TLE patientc.875C>G → CG
AssociationStudy
AssociationStudy
AssociationStudy
Sapio et al. J Biological Chemistry, 2012
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• Epilepsy
• Focal Epilepsy & Febrile Seizures
• Carboxypeptidase A6 (CPA6)
• Epigenetics of epilepsy
• CPA6 DNA Methylation & Epilepsy
• Perspectives
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EPIGENETICS
• Regulation of biological processes from conception to death of an organism
• Mitotically and/or meiotically heritable variations in gene functions, which are not due to changes in DNA sequence
• Essential for normal development, maintenance of cellular homeostasis and functions of an adult organism
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LIFE EPIGENETIC PROFIL
Foley et al. Am. J. Epidemiol. 2009
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DNA METHYLATION
CCH3 GC
GCH3
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METHYLATION HYPOTHESIS IN EPILEPTOGENESIS
Kobow & Blümcke, Epilepsia, 2012
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• Epilepsy
• Focal Epilepsy & Febrile Seizures
• Carboxypeptidase A6 (CPA6)
• Epigenetics of epilepsy
• CPA6 DNA Methylation & Epilepsy
• Perspectives
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CPA6 CpGs IN PROMOTER
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EPILEPTIC PATIENTS & CONTROLS
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INCREASED LEVEL OF CPA6 METHYLATION
0 1 2 3 4 5 6 7 8
Controls FE FS Treated Controls
with AEDs Healthy Children with FHE
Young Controls
* ; # ; § ; $
** ; ## ; § § ; $ $
% M
ethy
latio
n
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• Epilepsy
• Focal Epilepsy & Febrile Seizures
• Carboxypeptidase A6 (CPA6)
• Epigenetics of epilepsy
• CPA6 DNA Methylation & Epilepsy
• Perspectives
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PERSPECTIVES
• In epilepsy field à Beginning of epigenetics research à A few published studies and most related to DNA methylation
•New cohorts of patients
à Blood (DNA) collected after a first seizure
à Blood (DNA) collected after X seizures
à Comparison of DNA methylation level (EpiGenome wide)
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Thank you for your attention